Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: in vivo evidence for Pb and Zn competition

Zinc finger protein (ZFP) transcription factors are essential for regulation of gene expression in the developing brain. We previously reported that Pb exposure perturbed the DNA-binding of ZFP such as Sp1 and Egr-1 in the cerebellum, which play critical role in CNS development. In this study, we focused on hippocampal Sp1 DNA-binding and mRNA expression in neonatal Pb-exposed animals. The expression pattern of an Sp1 target (NMDAR1) gene was also monitored. To study in vivo and in vitro competition between Pb and Zn, we supplemented animals with Zn, and examined the effects of both metals on hippocampal Sp1 DNA-binding and the DNA-binding of a recombinant Sp1 protein (rhSp1). Tissue metal analysis revealed that only the disposition of Pb in the brain but not its distribution in the blood was influenced by the presence of Zn. The developmental profile of Sp1 DNA-binding exhibited a peak on PND 15 which subsequently declined to adult levels. Consistent with earlier studies, Pb exposure produced premature peaks of Sp1 DNA-binding on PND 5 which later returned to adult levels. The basal and Pb-induced developmental patterns of Sp1 mRNA departed from its DNA-binding profiles. However, the expression patterns of the NMDAR1 gene were relative to Sp1 DNA-binding. Supplementation with zinc provided a protective effect on Pb-induced changes in Sp1 DNA-binding. Moreover, Pb and Zn directly interfered with the DNA-binding of rhSp1 in vitro. These data suggest that Pb and Zn can compete both in vivo and in vitro at the zinc finger domain of Sp1 with a consequential effect on Sp1 DNA-binding, subsequent gene expression and brain development. (C) 2002 Published by Elsevier Science Ltd on behalf of ISDN.